MEETING REVIEW 3933
Development 140, 3933-3937 (2013) doi:10.1242/dev.096867
© 2013. Published by The Company of Biologists Ltd
Developing insights into cardiac regeneration
Vincent M. Christoffels1,* and William T. Pu2,*
Owing to its intrinsic beauty and biomedical importance, the
heart has been the focus of intensive research. The recent
EMBO/EMBL-sponsored symposium ‘Cardiac Biology: From
Development to Regeneration’ gathered cardiovascular scientists
from across the globe to discuss the latest advances in our
understanding of the development and growth of the heart,
and application of these advances to improving the limited
innate regenerative capacity of the mammalian heart. Here, we
summarize some of the exciting results and themes that
emerged from the meeting.
Key words: Heart, Development, Regeneration, Cardiac progenitor
cells, Transcriptional regulation
Introduction
The heart is one of the first organs to function, and continuous
pump function is essential for fetal and postnatal life. The
vertebrate heart forms as a single tube, which then loops, expands
chambers, and septates to acquire its mature organization. The heart
grows rapidly through fetal and early postnatal life. Fetal heart
growth is achieved by cardiomyocyte (CM) proliferation, but
postnatal mammalian CMs lose their capacity to proliferate, and
postnatal growth occurs primarily by increasing CM size rather
than number. Diseases such as myocardial infarction (MI) result in
the loss of billions of CMs leading to heart failure, for which we
lack specific therapies. The profound medical and economic impact
of heart disease has led cardiovascular scientists to focus on the
mechanisms that regulate heart growth and development and to use
this knowledge to design approaches for cardiac regeneration.
In June 2013, the EMBO/EMBL symposium ‘Cardiac Biology:
From Development to Regeneration’ brought together a diverse
group of over 200 cardiovascular scientists from six continents,
among them many of the current and future investigators at the
forefront of this rapidly developing field. The meeting was
organized by Nadia Rosenthal (EMBL Australia, Australia), Robert
Graham (Victor Chang Cardiac Research Institute, Australia),
Stephanie Dimmeler (Goethe-University Frankfurt am Main,
Germany) and Didier Stainier (Max Planck Institute for Heart and
Lung Research, Germany) and was held at the magnificent EMBL
Advanced Training Centre in Heidelberg, Germany. The meeting
featured wide-ranging topics that highlighted many of the most
recent developments in the field, with time for thought-provoking
questions and many opportunities for discussions among
conference participants. An overarching theme of the meeting was
how understanding heart development is the foundation for
advancing towards the goal of cardiac regeneration (Fig. 1). Here,
1
Department of Anatomy, Embryology, and Physiology, Heart Failure Research
Center, Academic Medical Centre, University of Amsterdam, Amsterdam 1105AZ,
The Netherlands. 2Department of Cardiology, Boston Children’s Hospital, 300
Longwood Avenue, Boston, MA 02115, USA.
*Authors for correspondence ([email protected]; [email protected])
we highlight some of the outstanding talks, advances and
interesting questions from the meeting.
Heart development
An important question in cardiac biology is whether cardiac
lineages are plastic, i.e. whether differentiated cells of a particular
lineage can transdifferentiate to another lineage. Didier Stainier
showed that ablation of ventricular cells in 3-4 days postfertilization (dpf) larvae leads to subsequent regeneration.
Strikingly, lineage tracing of atrial cells labeled prior to ventricular
ablation showed that regenerated ventricular cells appeared to
derive from atrial cells that were reprogrammed (Zhang et al.,
2013). Inhibiting Notch signaling blocked this transdifferentiation.
These observations indicate plasticity of cardiac lineage-specific
differentiated cells in the embryo in the context of myocardial
injury.
Stainier also described the process of cardiac trabeculation in
vivo at the cellular level using high-resolution 3D time-lapse
imaging (4D imaging) of beating zebrafish hearts. The combination
of 4D imaging and analysis of erbb2 null genetic mosaics (Liu et
al., 2010) illustrated the dynamic movement of CMs whereby the
cells extend processes that invade at the luminal side into the
forming trabecular layer and subsequently reposition to contribute
to the trabecular layer. His data also showed that cardiac
contraction might also promote cardiac trabeculation, because
genetic or pharmacological paralysis of the heartbeat blocked
trabeculation.
That fluid forces play important roles in organ morphogenesis
was further illustrated by Nadia Mercader (National Center for
Cardiovascular Research, Spain). Using high-speed imaging and
optical tweezing in zebrafish embryos, Mercader showed that
heartbeat-driven pericardial fluid forces trigger proepicardium
formation at several sites within the pericardial wall, modulate
epicardial progenitor cell release and motion, and determine the
location of their adhesion to the myocardial wall. These studies,
which were accomplished as part of a collaboration with the group
of Julien Vermot (Institute of Genetics and Molecular and Cellular
Biology, France), represent the first example of extra-cardiac flow
forces controlling cardiogenesis.
The heart is the first organ to develop left-right asymmetry.
Cecilia Lo (University of Pittsburgh, USA) provided an update on
a mouse N-ethyl-N-nitrosourea (ENU) mutagenesis screen in which
150 mutant lines with a wide spectrum of structural congenital
heart defects (CHDs) were recovered, including the first mouse
models of hypoplastic left heart syndrome. Strikingly, almost half
of the lines exhibited complex heart defects in association with
laterality defects. Exome sequencing revealed mutations in cilia
genes not only in many lines with laterality defects, but also in a
significant fraction of lines with CHDs but no laterality defects.
These findings suggest a role for cilia defects in CHDs independent
of the important role of cilia in establishing left-right asymmetry.
The theme of left-right asymmetry continued with Salim
Seyfried (Max Delbrück Center for Molecular Medicine, Germany)
Development
Summary
3934 MEETING REVIEW
Looped
heart
Adult
heart
Development
Cardiac progenitors; lineage specification;
differentiation; cardiomyocyte proliferation;
paracrine factors
Regeneration
Injury
Adult
heart
MI
Post-MI
heart
Fig. 1. Lessons from heart development inform efforts to promote
cardiac regeneration. Studies of heart development have yielded
biological insights that may be effectively deployed to regenerate the
heart after myocardial injury.
who discussed the role of bone morphogenetic protein (BMP)
signaling in modulating cell motility and thereby directing cardiac
left-right asymmetry (Veerkamp et al., 2013). Left-sided Nodal
reduces BMP signaling specifically at the left side of the cardiac
field of zebrafish embryos. Reduced BMP signaling resulted in
lower expression of non-muscle myosin II and higher cell motility
on the left. Computational modeling indicated that this difference
in cell motility is sufficient to induce directional migration of
cardiac tissue to the left, which is the first step in establishing
cardiac left-right asymmetry. These studies provide a mechanistic
link between anti-motogenic BMP activity and cardiac left-right
asymmetry.
Epigenetic and transcriptional regulation
Heart development is regulated by gene regulatory networks
consisting of a set of highly conserved tissue-specific transcription
factors, signaling molecules and non-coding RNAs. Central to this
network are the transcription factors NKX2-5, GATA4 and SRF,
which, together with their target DNA elements, form an
evolutionarily conserved subcircuit essential for development,
dubbed a ‘kernel’ (Davidson and Erwin, 2006). Richard Harvey
and Mirana Ramialison (Victor Chang Cardiac Research Institute,
Australia) studied this kernel by comparing the target sites of wildtype NKX2-5 with those of a mutated form of NKX2-5 in which
the homeodomain is missing. Off-target sites for mutant NKX2-5
were identified that were enriched in motifs for ubiquitous
transcription factors, including members of the ETS family, which
was attributed to interaction between mutant NKX2-5 and ETS
domain-containing proteins. This suggested that ubiquitously
expressed factors might be embedded in the heart kernel. Further
light was shed on gene regulation by Silke Sperling (Charité
Universitätsmedizin, Berlin; and Max Delbrück Center for
Molecular Medicine, Germany) who discussed the crosstalk
between cardiac transcription factors, chromatin remodeling
enzymes and histone modifications. Some redundancies in the
network became apparent and particular transcription factors, such
as GATA4 and NKX2-5, co-occupied target sites, implicating the
preferential interactions of these factors with chromatin remodeling
enzymes, such as BAF60 and its associated SWI/SNF complex.
The architecture of the chromatin is an important aspect of
gene regulation and thus of the gene regulatory networks. Vincent
Christoffels (Academic Medical Center, Amsterdam) used 4Cseq, a technique that probes three-dimensional chromatin
architecture to enhance dissection of the regulatory circuitry of
Tbx3, a crucial component of the gene regulatory network for the
cardiac conduction system (CCS) (van den Boogaard et al.,
2012). Sites of interaction between putative regulatory elements
and the Tbx3 promoter appeared to be limited to the region
between the flanks of the Tbx3 locus. In vivo enhancer analysis
showed that these sites harbor evolutionarily conserved Tbx3
enhancers that are necessary and sufficient to drive expression in
the CCS, recapitulating the Tbx3 expression pattern. These data
provide an example of the involvement of chromatin 3D
architecture in the regulation of developmental gene expression.
Margaret Buckingham (Institut Pasteur, France) discussed the
transcriptional pathways that control activation of fibroblast growth
factor 10 (Fgf10), a key gene regulating the behavior of secondary
heart field progenitors, which contribute CMs to the ends of the
growing heart tube. Buckingham’s work investigated
transcriptional pathways that regulate Fgf10, a gene known to
regulate the anterior second heart field (SHF) progenitors. She
showed that Fgf10 expression depends on an enhancer regulated
by TBX1, NKX2-5 and ISL1 (Watanabe et al., 2012). The
enhancer acts as a switch that is activated in the SHF by high levels
of ISL1 and TBX1 and is repressed in myocardium by high levels
of NKX2-5, which acts both directly and indirectly through Isl1
suppression. This example provides a paradigm for changes in
regulatory networks during the transition from the progenitor state
to that of differentiated myocardium.
Non-coding RNAs have been implicated in various gene
regulatory networks across a vast number of developing and
mature organ systems, and the heart is no exception. Bernhard
Herrmann (Max Planck Institute for Molecular Genetics, Germany)
and Stefanie Dimmeler both presented evidence for the role of noncoding RNAs in the developing and aged heart, respectively.
Herrmann presented work on Fendrr, a tissue-specific long noncoding RNA (lncRNA) that is transiently expressed in the lateral
mesoderm that gives rise to the heart and body wall. Inactivation
of Fendrr in mouse revealed its requirement for heart and body
wall development (Grote et al., 2013). Fendrr interacts with both
polycomb and trithorax epigenetic regulatory complexes and the
double-stranded DNA (dsDNA) of target promoters, suggesting
that it recruits these antagonistic complexes to different promoters
in order to modulate their epigenetic landscape and to regulate
target gene expression in the developing heart. Dimmeler discussed
the function in the adult of microRNA-34a, which is induced in the
aging heart (Boon et al., 2013). Deletion or reduction of miR-34a
reduced the CM cell death and fibrosis caused by myocardial
ischemia or aging. PNUTS (also known as PPP1R10), a protein
that reduces both telomere shortening and the DNA damage
response, was identified as a key target of miR-34a.
Development
Cardiac
crescent
Development 140 (19)
Heart regeneration from endogenous cell sources
A fundamental question facing cardiac biologists is the extent to
which CMs proliferate in the normal heart. Ahsan Husain (Emory
University, USA) described a meticulous study of juvenile murine
heart growth, which identified an unexpected spike in proliferative
activity of binucleated CMs on post-natal day (P)15, suggesting
that these cells might not be terminally differentiated. Moving on
to humans, Olaf Bergmann (Karolinska Institute, Sweden)
presented a study on CM proliferation in pediatric patients and
adult humans based on analysis of human hearts using unbiased
stereology. Measurement of both CM volume and CM nuclear
density indicated that CM number did not change substantially in
young humans. However, Bernhard Kuhn (Boston Children’s
Hospital, USA) investigated the same question and reached a
different conclusion (Mollova et al., 2013). Measurement of CM
volume and numbers, karyokinesis, cytokinesis and ploidy showed
that the CM number increases by 3.4-fold over the first 20 years of
life, indicating that heart growth in young humans occurs through
a combination of an increase in CM number and size. Given these
apparently contradictory results, further work is clearly required to
determine conclusively the degree of proliferation and timing of
terminal CM differentiation in the postnatal heart.
The capacity of the postnatal heart to regenerate in normal and
injury conditions has also been investigated in mouse models. Eric
Olson (University of Texas Southwestern Medical Center, USA)
previously reported that the mouse is able to regenerate resected
myocardium up to P7 (Porrello et al., 2011). The type of injury
probably influences the regenerative response, as Olson showed
that regeneration occurs after neonatal myocardial infarction,
whereas Bernhard Kuhn indicated that the neonatal mouse heart
fails to regenerate effectively after cryoinjury. Interestingly,
neonatal myocardial regeneration appears to require an initial
inflammatory response involving macrophages, because depletion
of macrophages using clodronate liposomes nearly completely
blocks the neonatal heart regeneration after MI.
The involvement of macrophages in heart and skeletal muscle
regeneration was further expanded upon in presentations by Nadia
Rosenthal and Thomas Braun (Max Planck Institute for Heart and
Lung Research, Germany). Braun reported on newt heart
regeneration; explant studies revealed that mechanically injured
newt hearts must remain in situ for at least a few days in order to
regenerate. If the hearts are explanted immediately following
injury, they fail to regenerate effectively. At least one reason for
this is the need for macrophage infiltration, as macrophage
depletion by clodronate liposomes also prevented newt heart
regeneration. Braun described an additional positive-feedback loop
involving macrophages that functions to minimize injury in the
adult mouse heart after MI. Oncostatin M, secreted by CMs from
injured myocardium, recruits macrophages. These macrophages
then secrete Reg3b, a cytokine that stimulates further macrophage
recruitment. Forced inactivation of Reg3b compromised heart
function after MI and at the same time impaired scar formation,
resulting in higher risk of cardiac rupture. Rosenthal also reported
a role for macrophages in axolotl limb regeneration (Godwin et al.,
2013), in which macrophage infiltration occurs early after limb
amputation and is necessary for regeneration. Rosenthal then went
on to identify a putative role for Treg anti-inflammatory cells in
insulin-like growth factor (IGF)-mediated scar-free healing in
skeletal muscle.
Strategies for stimulating endogenous heart regeneration or
minimizing heart injury were presented. One approach is to
enhance CM proliferation. William Pu (Boston Children’s Hospital,
MEETING REVIEW 3935
USA) and Eric Olson reported independent studies showing that
YAP1 is sufficient to drive adult CM proliferation and to improve
survival and myocardial outcome after MI. Felix Engel
(Universitätsklinikum Erlangen, Germany) described a screen to
identify small molecules that enhance neonatal CM proliferation.
One compound identified was carbacyclin, which stimulates
PPARδ to activate β-catenin signaling. Despite the identification of
signaling and transcriptional pathways that stimulate CM
proliferation in neonatal CMs, adult CMs are strikingly resistant to
proliferation. David Zebrowski, a member of the Engel lab, showed
that at least one fundamental block results from loss of centriole
cohesion in mature binucleated cardiomyoytes and consequent
activation of a centriole-mediated mitotic checkpoint.
Kenneth Chien (Karolinska Institute, Sweden) described a novel
approach to minimizing heart injury, based on a therapeutic
paradigm of delivering a paracrine signal at the right time and place
to modulate cardiac progenitor cell fate. He reported that modified
RNA encoding VEGFA given at the time of MI delivers a strong
VEGFA pulse that lasts ~48 hours. This pulse augments epicardial
progenitor function, mobilizes them from the heart surface, and
directs their differentiation towards the endothelial lineage, thereby
improving myocardial perfusion, function and long-term survival.
Eric Olson summarized his group’s progress on in vivo
reprogramming of fibroblasts to CMs (Ieda et al., 2010; Song et al.,
2012). In vitro, his lab found that forced expression of the major
cardiac transcription factors GATA4, HAND2, MEF2c and TBX5
(GHMT) reprogram tail tip mouse fibroblasts into CMs. In vivo,
this process is considerably more efficient and leads to long-term
enhancement of heart function after MI. His lab has made progress
in identifying small molecules that significantly enhance the
efficiency of the reprogramming process, and by finding that
human fibroblasts can be reprogrammed using GHMT plus
myocardin.
Building a heart: stem and progenitor cells and
their application to heart regeneration
Other potential approaches to cardiac regeneration involve
augmenting the responses of endogenous cardiac progenitors, or
delivering progenitor cell populations or their derivatives to the
infarcted heart after amplification in vitro. To modulate endogenous
cardiac progenitor populations, it is first necessary to define these
populations. This goal has been both elusive and contentious.
Michael Schneider (Imperial College London, UK) described his
efforts to characterize the murine Sca1 (Ly6a – Mouse Genome
Informatics)-positive heart progenitor population (Oh et al., 2003)
and showed that the progenitor subset can be substantially enriched
by sorting for either high efflux of Hoescht dye (‘side population’)
or by high expression of PDGFRa. The enriched population
expresses various combinations of the cardiac transcription factors
GHMT and has multi-lineage potential in cardiac grafts. Bernardo
Nadal-Ginard (King’s College London, UK) described an
alternative cardiac progenitor cell population in mice characterized
by expression of the marker c-Kit (Kit – Mouse Genome
Informatics) (Beltrami et al., 2003). He reported a clever and
demanding set of experiments that led him to conclude that c-Kit+
cells are necessary and sufficient to drive regeneration in an acute
adult myocardial injury model based on a cardiotoxic dose of
isoproterenol (Ellison et al., 2007).
There has been tremendous interest in delivering progenitor cells
or mature in vitro differentiated CMs into the heart to drive heart
repair. Charles Murry (University of Washington, USA) described
a Herculean effort in his lab to provide proof of concept that human
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Development 140 (19)
embryonic stem cell (ESC)-derived CMs can be safely transplanted
and electrically integrated into the heart of a non-human primate
after MI. His group delivered 109 human ESC-derived CMs into
the two-week-old infarcted heart of immunosuppressed Macaca
nemestrina. Initially, the treatment induced cardiac arrhythmias,
including ventricular tachycardia and accelerated idioventricular
rhythm, but this pro-arrhythmic effect resolved after about two
weeks, by which time electrical coupling was observed between
graft and native myocardium. Grafts appeared to be perfused by a
sluggish vascular plexus, and developing a brisk arterial supply is
a substantial remaining hurdle. Lior Gepstein (Technion-Israel
Institute of Technology, Israel) touched on his lab’s efforts to meet
this challenge using engineered biomaterials and a mixture of CM,
endothelial and mesenchymal cells to generate grafts with
improved vascularization.
More than 2600 patients have already received bone marrowderived mononuclear cell (BMC) transplantation for ischemic heart
disease (Jeevanantham et al., 2012). Although injected bone
marrow-derived cells do not persist in host tissue, their transient
homing to injured myocardium appears to exert paracrine and
immunomodulatory effects that may enhance myocardial recovery
from infarction. Andreas Zeiher (Goethe University Hospital,
Germany) reviewed his group’s experience with this form of cell
therapy. In patients with only modestly reduced ejection fraction,
BMC cells showed little benefit. However, in patients with more
severely reduced ejection fraction (<45%), BMC-treated patients
had reduced adverse remodeling and better preservation of heart
function. Individual patient outcomes were highly heterogeneous,
however, and one important factor might be the homing efficiency
of the injected BMCs. Zeiher showed data that this might be
improved by echocardiography-guided shock wave pretreatment to
enhance myocardial release of chemotactic factors.
Paul Simmons (Mesoblast, Australia) discussed Mesoblast’s
evaluation of bone marrow-derived, immunopurified mesenchymal
precursor cells for cardiovascular indications. In an ovine MI
model, intracardiac delivery of these cells resulted in better cardiac
ejection fraction at 8 weeks, largely due to paracrine and
immunomodulatory effects. Among the many factors excreted by
these cells are HGF, IGF1, IL6, MCP1, SDF1 and VEGF. Although
there may be reason to believe that BMC therapy has a beneficial
effect in subsets of patients with MI, the mechanisms underlying
this phenomenon require further investigation.
Modeling heart disease with induced pluripotent
stem cells (iPSCs)
Our improving understanding of stem cell biology, cardiogenesis and
CM function have converged upon developing in vitro models for
human disease. Of great value in this respect are induced pluripotent
stem cells (iPSCs), which can be derived from patients with a variety
of diseases and differentiated to CMs to recapitulate disease
phenotypes and mechanisms. Joseph Wu (Stanford, USA)
summarized his lab’s efforts in using iPSCs derived from patients
with dilated and hypertrophic cardiomyopathy to model core features
of these diseases (Sun et al., 2012; Lan et al., 2013). He also outlined
the value of iPSC-derived CMs for screening of new drug candidates
for cardiotoxicity, and presented a vision in which this screening is
performed against a bank of 1000 iPSC-derived human CMs to
capture human genetic variation and perhaps identify subgroups in
which a drug might be safe or unsafe. Lior Gepstein discussed his
group’s experience using patient-derived iPSCs to model long QT
syndrome and arrhythmogenic right ventricular cardiomyopathy
(ARVC) (Itzhaki et al., 2011). He observed that the CMs
Development 140 (19)
differentiated from ARVC iPSCs accumulated lipid droplets, which
were reminiscent of fatty replacement seen in patients, and this was
linked to increased activity of PPARγ in the disease cells.
However, in vitro models continue to have limitations, most
notably the immature phenotype of current iPSC-derived CMs.
Malin Jonsson Boezelman (Genome Institute of Singapore,
Singapore) pointed out the importance of this problem in the
context of using pluripotent stem cell-derived CMs for
cardiotoxicity assays. These CMs lack or have low levels of some
key ionic currents present in adult CMs, and consequently these
screens can yield both false-positive and false-negative results.
Developing appropriate conditions to mature properly in vitro
differentiated CMs is necessary to overcome this limitation.
Conclusion
This meeting summary highlights some of the exciting advances
being made in cardiovascular biology. Using development as a
roadmap towards regeneration has brought us to a point at which
clinical therapy can be contemplated and even implemented in
some cases. However, we also learned that the heart does not yield
its mysteries easily. We still have a long way to go to realize the
vision of cardiac regeneration, and insights from developmental
biology will surely light the way.
Acknowledgements
The authors apologize for being able to summarize only a small subset of the
many insightful presentations and posters on display at the meeting.
Funding
W.T.P. was funded by the National Institutes of Health. V.M.C. was funded by
the European Community’s Seventh Framework Programme contract
(‘CardioGeNet’) and the Netherlands Organisation for Scientific Research
(NWO) ZonMw.
Competing interests statement
The authors declare no competing financial interests.
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